PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is the 6th leading cause of cancer-related death in the United States. Although up to 40% of adult patients are responsive to standard chemotherapy, almost all relapse and progress to resistant disease. Most AML patients display no cytogenetic abnormalities or driver mutations, which poses a significant challenge for designing targeted therapy. Combination therapy may also be useful for preventing resistance and improving overall survival. Recent advances in epigenomics have shed light on cellular reprogramming in cancer. Epigenetic proteins can modulate gene expression to induce pathways that increase cell proliferation and decrease differentiation. Coactivator-associated arginine methyltransferase 1 (CARM1) is an epigenetic protein overexpressed in AML. CARM1 has been identified as a key regulator of myeloid differentiation and cancer progression; and is overexpressed in primary, resistant, and recurrent AML. CARM1?s mechanistic role in AML induction and progression (including relevant substrates and regulation) is still unclear, which presents an additional challenge for clinicians to design new therapies. To address gaps in our current understanding of CARM1 function and the need for new AML therapies, I aim to (1) Identify compounds that target CARM1 expression and compounds that work in synergy with a known CARM1 inhibitor in AML and (2) Identify novel chemotypes that directly inhibit CARM1 using a hybrid approach of machine learning and simulations of small molecule-protein interactions. These aims support key goals of the National Cancer Institute (NCI) and Precision Medicine Initiative, including (1) understanding cancer progression, (2) genomic analysis, (3) advancing precision medicine, (4) bioinformatics and (5) translational research.